Improved Asymmetric Synthesis of Aziridine 2-Phosphonates Using (S

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Improved Asymmetric Synthesis of Aziridine 2-Phosphonates Using (S)-(+)-2,4,6-Trimethylphenylsulfinamide Franklin A. Davis,* Tokala Ramachandar, and Yongzhong Wu Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122 [email protected] Received April 24, 2003

The aza-Darzens reaction of lithium diethyl iodomethylphosphonate with enantiopure N-(2,4,6trimethylphenylsulfinyl)imines affords a single diastereomeric N-sulfinylaziridine 2-phosphonate which, on treatment with MeMgBr, gives the corresponding NH-aziridine 2-phosphonate chiral building blocks. An improved asymmetric synthesis of (S)-(+)-2,4,6-trimethylphenylsulfinamide is also given. Aziridine 2-phosphonates are valuable polyfunctionalized chiral building blocks for the asymmetric synthesis of amino phosphonates because of their ability to undergo highly regio- and stereospecific ring-opening reactions.1-6 Oxidation of NH-aziridine 2-phosphonates provides 2Hazirine 2-phosphonates and 2H-azirine 3-phosphonates.4,7 The latter azirines are a new class of chiral imino dienophiles that undergo Diels-Alder reactions to produce bicyclic aziridines that can be transformed into the first examples of quaternary piperidine phosphonates.7 Chiral nonracemic amino phosphonic acids are important amino acid analogues because many exhibit antibacterial, anticancer, and antiviral activity as well as pesticidal, insecticidal, and herbicidal properties.8 Recently, we described a new methodology for the asymmetric synthesis of aziridine 2-phosphonates that involves the addition of the anion of halomethylphosphonates 1 to enantiopure N-p-toluenesulfinylimines (S)-(+)2.2 In this aza-Darzens reaction, the aziridines were formed as cis and trans mixtures of 3/4 that were difficult to separate (Scheme 1). To circumvent this problem, the intermediate R-chloro β-amino phosphonates 5 and 6 were isolated and cyclized with n-butyllithium to give the enantiopure aziridines (SS,2S,3R)-3 and (SS,2R,3R)-4. However, it was noted in one case that if the bulky N-tert(1) (a) For a reviews on aziridines, see: (a) McCoull, W.; Davis, F. A. Synthesis 2000, 1347. (b) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599. (c) Pearson, W. H.; Lian, B. W.; Bergmeier, S. C. Aziridines and Azirines: Monocyclic. In Comprehensive Heterocyclic Chemistry II; Padwa, A., Ed.; Pergamon Press: Oxford, 1996; p 1. (d) Rai, K. M. L.; Hassner, A. Aziridines and Azirines: Fused-ring Derivatives. In Comprehensive Heterocyclic Chemistry II; Padwa, A., Ed.; Pergamon Press: Oxford, 1996; p 61. (2) Davis, F. A.; Wu, Y.; Yan, H.; McCoull, W.; Prasad, K. R. J. Org. Chem. 2003, 68, 2410. (3) Pouset, C.; Larcheveque, M. Tetrahedron Lett. 2002, 34, 5257. (4) Davis, F. A.; McCoull, W. Tetrahedron Lett. 1999, 40, 249. (5) Davis, F. A.; McCoull, W.; Titus, D. D. Org. Lett. 2000, 1, 1053. (6) Hanessian, S.; Bennani, Y. L.; Herve, Y. Synlett 1993, 35. (7) Davis, F. A.; Wu, Y.; Yan, H.; Prasad, K. R.; McCoull, W. Org. Lett. 2002, 4, 655. (8) For reviews, see: (a) Kafarski, P.; Lejczak, B. Phosphorus Sulfur Silicon 1991, 63, 193. (b) Seto, H.; Kuzuyama, T. Nat. Prod. Rep. 1999, 16, 589. (c) Aminophosphonic and Aminophosphinic Acids. Chemistry and Biological Activity; Kukhar, V. P., Hudson, H. R., Eds.; Wiley: Chichester, U.K., 2000.

butanesulfinylimine (S)-(+)-7 was used, the aziridine (+)-8 was formed in good yield as a single diastereoisomer. Unfortunately, all attempts, under acid or base conditions, to remove the N-tert-butanesulfinyl auxiliary without aziridine ring opening failed. The advantage of the N-tert-butanesulfinyl versus the N-p-toluenesulfinyl group is that Grignard reagents add to the C-N bond to give amines in the former, while with the latter auxiliary, attack at the sulfinyl sulfur produces sulfoxides.9 This difference in reactivity was employed in a highly selective method to deprotect N-p-toluenesulfinylaziridines by treating them with methylmagnesium bromide.2,10 This protocol affords the valuable NHaziridines, in excellent yield, without ring-opening, even with highly activated examples. What we required was an N-sulfinyl auxiliary that is large enough to produce high diastereoselectivities in the aza-Darzens reaction while permitting selective deprotection using our Grignard protocol. The N-(2,4,6-trimethylphenylsulfinyl) auxiliary meets these requirements, as described herein. Results and Discussion Senanayake and co-workers recently introduced methodology for the asymmetric synthesis of diversely substituted sulfinamides (RS(O)NH2), which are the precursors of sulfinimines (N-sulfinyl imines).11 This procedure involves reacting Grignard reagents, such as 2,4,6trimethylphenylmagnesium bromide, with endo-(-)-1,2,3oxathiazolidine-2-oxide 9 to give the corresponding sulfinate ester (-)-10 (Scheme 2). It was reported that on treatment of 10 with sodium bis(trimethylsilyl)amide (NaHMDS), (S)-(+)-2,4,6-trimethylphenylsulfinamide (11) (9) For reviews on the chemistry of sulfinimines, see: (a) Zhou, P.; Chen, B-C.; Davis, F. A. In Advances in Sulfur Chemistry; Rayner, C. M., Ed.; JAI Press: Stamford, CT, 2000; Vol. 2, pp 249-282. (b) Davis, F. A.; Zhou, P.; Chen. B.-C. Chem. Soc. Rev. 1998, 27, 13. (c) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984. (10) Davis, F. A.; Liu, H.; Zhou, P.; Fang, T.; Reddy, G. V.; Zhang, Y. J. Org. Chem. 1999, 64, 7559. (11) Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.; Senanayake, C. H. J. Am. Chem. Soc. 2002, 124, 7880. 10.1021/jo030142m CCC: $25.00 © 2003 American Chemical Society

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Published on Web 08/15/2003

Asymmetric Synthesis of Aziridine 2-Phosphonates SCHEME 1

SCHEME 2

was obtained in 80% yield. The enantiomerically purity was judged to be 99% by chiral HPLC analysis.11 However, in our hands, treatment of (-)-10 with NaHMDS at -78 °C to room temperature gave a 55% yield of sulfinamide 11 with a specific rotation of +98.0°.12 Chiral HPLC analysis indicated that sulfinamide (S)-(+)11 was only 55% enantiomerically pure. Attempts to improve the purity by varying the equivalents of base, temperature, and time were without success. In our earlier studies on the one-pot synthesis of enantiopure sulfinimines from the Andersen reagent, (1R,2S,5R)(12) In our work, we prepared and used the enantiomers of the compounds described in ref 11. Specific rotations and melting points were not provided.

(-)-menthyl-(S)-p-toluenesulfinate, LiHMDS, and aldehydes it was noted that if NaHMDS were used the ee’s dropped form >98% to 66% ee.13 We attributed this result to racemization of the sulfinimine by the more reactive nucleophile. With this in mind, we treated (-)-10 with 2.2 equiv of LiHMDS at -78 °C to room temperature and obtained a 70% isolated yield of (S)-(+)-11, following chromatography and crystallization. Importantly the specific rotation of the product had increased to +177.8° and chiral HPLC indicated that the enantiomeric purity was >98%. With enantiopure (S)-(+)-2,4,6-trimethylphenylsulfinamide (11) in hand, we proceeded to condense it in the usual manner with 4-methoxybenzaldehyde, benzaldehyde, 4-trifluoromethylbenzaldehyde, and 4-nitrobenzaldehyde in the presence of excess Ti(OEt)4.14 The corresponding sulfinimines (S)-(+)-12a-d were isolated in 78-82% yield (Scheme 2). Next, a solution of (S)-(+)12 and 2 equiv of diethyl iodomethylphosphonate were treated at -78 °C with 2 equiv of LiHMDS (Scheme 3). Importantly, sulfinimines 12a and 12b, having the 4-methoxyphenyl and phenyl groups, afford aziridines (SS,2S,3R)-(-)-13a and (SS,2S,3R)-(-)-13b as single diastereoisomers in one pot and in 75-78% isolated yield (Table 1, entries 1 and 3). The cis stereochemistry is supported by the H2,3 proton coupling constants of J ) (13) Davis, F. A.; Reddy, R. E.; Szewczyk J. M.; Reddy, G. W.; Portonovo, P. S.; Zhang, H.; Fanelli, D.; Thimma-Reddy, R.; Zhou, P.; Carroll, P. J. J. Org. Chem. 1997, 62, 2555. (14) (a) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli, D. L.; Zhang, H. J. Org. Chem. 1999, 64, 1043. (b) Fanelli, D. L.; Szewczyk, J. M.; Zhang, Y.; Reddy, G. V.; Burns, D. M.; Davis, F. A. Organic Syntheses 1999, 77, 50.

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Davis et al. SCHEME 3

TABLE 1. Addition of Lithium Halomethylphosphonate

SCHEME 4

Anions to Sulfinimines (S)-(+)-12

entry 1 2 3 4 5 6 7

sulfinimine (X )) 12a (4-MeO) 12b (H) 12c (4-CF3) 12d (4-NO2) 7b (4-CF3)

1 (Z )) I Cl I I Cl I I

aziridine 13a (% yield)b

β-amino R-chlorophosphonate 15/16 (% yield)b

(+)-13a (75%) 77:23 (70%) [77:23]d (+)-13b (78%) 43:57c (82%) 23:77 (70%) [1:1]d 53:47c (78%) (+)-8b (72%)

Aziridines were >98:2. b Isolated yield. c Ratio of aziridine diastereoisomers to β-amino R-iodophosphonate mixtures. d Ratio of 15/16 using the p-toluenesulfinyl auxiliary. See ref 2. a

7.6 Hz2 and their conversion into known compounds (see below). By contrast, sulfinimines 12c and 12d, having the electron-attracting 4-trifluoromethylphenyl and 4-nitrophenyl groups, gave complex mixtures of products consisting of the aziridines diastereomers 13c,d and isomeric mixtures of the β-amino R-iodophosphonates 14. All attempts to separate these mixtures proved unsuccessful. In an attempt to fix this problem, as we had done previously, the β-amino R-chlorophosphonates 15c/16c were prepared from (S)-(+)-12c and the lithium anion of dimethyl chloromethylphosphonate (Scheme 3). For comparison, a similar study was carried out with (+)12a, and these results are summarized in Table 1. Unfortunately, chromatographically inseparable mixtures of the corresponding β-amino R-chlorophosphonates 15/16 were produced in both cases (Table 1, entries 2 and 5). This contrasts sharply with the results obtained when the N-p-toluenesulfinyl auxiliary was employed and separable mixtures of 15/16 (p-tolyl instead of mes) were produced.2 This result may reflect the greater lipophilicity of the mes group versus the p-tolyl group. It is interesting to note that for 12a (X ) 4-MeO) similar ratios of 15/16 were observed for the N-2,4,6-trimethylphenylsulfinyl and N-p-tolylsulfinyl auxiliaries (Table 1, entry 2), whereas the ratios for 12c (X ) 4-CF3) were 23:77 and 1:1, respectively (Table 1, entry 5). We propose that the greater selectivity observed in the aza-Darzens reaction of lithium iodomethylphosphonate with sulfinimines having bulky N-sulfinyl auxiliaries is primarily due to two types of steric interactions in transition state TS-1. First, the iodomethylphosphonate anion is highly favored to attack the C-N double opposite 6896 J. Org. Chem., Vol. 68, No. 18, 2003

to the bulky N-sulfinyl group R. However, this alone would not predispose the transition state toward a single diastereomeric aziridine. The transformation also requires that the iodo group occupy the axial position in the transition state. Because halomethylphosphonate anions, unlike enolates, lack configuration stability, we suggest that the reason this position is preferred is that there are fewer gauche interactions between the iodo and ethoxy phosphonate groups when the former is in axial position. The explanation for the much lower selectivity on addition of the lithium anion of 1 to sulfinimines 12c and 12d, which have electron-attracting groups, is less apparent. One possibility is that π-acid π-base interactions (π-stacking) between the 2,4,6-trimethylphenyl group and the imino aryl group as in TS-2 may sterically alter the equatorial-axial ratio of the iodo group which would result in poorer selectivity. In support of this hypothesis is the fact that sulfinimine 7b (X ) 4-CF3), having the N-tert-butanesulfinyl auxiliary where π-stacking is unlikely, affords a single diastereomeric aziridine (SS,2S,3R)(+)-8b in 72% yield (Scheme 1).

Removal of the N-Sulfinyl Auxiliary. Reaction of aziridines (S)-(+)-13a and (S)-(+)-13b with 2 equiv of MeMgBr at -78 °C readily removed the 2,4,6-trimethylphenyl-sulfinyl group affording the corresponding NHaziridines (2S,3R)-(-)-17a and (2S,3R)-(-)-17b in 72 and 77% isolated yield (Scheme 4). Their physical properties were in agreement with literature values,2 which further serves to confirm the cis geometry of these aziridines.

Asymmetric Synthesis of Aziridine 2-Phosphonates

In summary, improved methodology has been introduced for the asymmetric synthesis of NH-aziridine 2-phosphonates, which are valuable polyfunctionalized chiral building blocks for R-amino phosphonates and 2Hazirine 3-phosphonate synthesis. This new procedure employs the N-(2,4,6-trimethylphenylsulfinyl)imines (S)(+)-12 and lithium diethyl iodomethylphosphonate. However, aryl sulfinimines containing electron-attracting groups give complex mixtures with this protocol. Although β-amino R-chloro phosphonates were produced with improved diastereomeric ratios compared to the N-(p-tolylsulfinyl) auxiliary, they were chromatographically inseparable, which may reflect the greater lipophilicity of the former auxiliary. In addition it was found that the use of LiHMDS in place of NaHMDS in the synthesis of (S)-(+)-2,4,6-trimethyl-phenylsulfinamide (11) results in an enantiomerically pure product.

Experimental Section Diethyl 2-chloro- and 2-iodomethylphosphonates were purchased from commercial sources. (S)-(+)-2-Methyl-N-[(1E)-[4(trifluoromethyl)phenyl]methylene]-2-propanesulfinamide (7b) [[R]20D 81 (c 0.68, CHCl3)] was prepared in 78% yield as described earlier.15,16 (1S,2R)-(-)-N-2-Mesitylaminodianol (9) [mp 160-161 °C; [R]20D -37.4 (c 1.0 CHCl3), IR (neat) 3101, 1574 cm-1] and (RS,1S,2R)-(-)-2,4,6-trimethylbenzenesulfinic acid 1-(2,4,6trimethylbenzenesulfonylamino)indan-2-yl ester (10) [mp 145-146 °C; [R]20D -55.4 (c 1.0 CHCl3); IR (neat) 3210, 3092 cm-1] were prepared as previously described11 from commercially available (1S,2R)-(-)-cis-1-amino-2-indanol and had spectral properties consistent with literature values.11 (S)-(+)-2,4,6-Trimethylphenylsulfinamide (11). In a 100-mL, one-necked, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed 1.0 g (0.0021 mol) of (-)-10 in THF (15 mL). The solution was cooled to -78 °C, and 4.2 mL (0.0042 mol, 1 M solution) of lithium bis(trimethylsilyl)amide (LiHMDS) was added via syringe. The reaction mixture was slowly warmed to room temperature, stirred for 4 h, and quenched at -78 °C by addition of 30% NH4Cl (10 mL). The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 × 25 mL), and the combined organic phases were dried (Na2SO4) and concentrated. Purification by chromatography (EtOAc) and crystallization from EtOAc at -20 °C afforded 0.26 g (70%) of a white solid: mp 125-126 °C; [R]20D +177.8 (c 0.5, CHCl3); IR (neat) 3205, 3092 cm-1. The 1H NMR and 13C NMR spectra were identical with the enantiomer (+)-11 previously reported.11 The enantiomeric purity was determined using a Chiralcel OD, 4-6 × 250 mm, 10 µm; 9:1 (hexane/i-PrOH), 1.0 mL/min, 250 nm; (S)-10, retention 17.5 min. Typical Procedure for the Synthesis of Sulfinimines from Aldehydes Using Titanium(IV) Ethoxide. (S)-(+)N-(Benzylidene)-2,4,6-trimethylphenylsulfinamide (12b). In a 50-mL, round-bottom flask equipped with a stirring bar and argon balloon was placed 0.10 g (0.546 mmol) of (+)-11, 0.055 mL (0.546 mmol) of benzaldehyde, and 0.572 mL (2.73 mmol) of titanium(IV) ethoxide in CH2Cl2 (15 mL). After being stirred at room temperature for 4 h (monitoring for completion by TLC), the reaction mixture was quenched by addition of H2O (10 mL). The turbid solution was filtered through Celite, and the filter cake was washed with CH2Cl2 (2 × 10 mL). The mixture was extracted with CH2Cl2 (10 mL), and the combined organic phases were dried (Na2SO4) and concentrated to give 0.121 g (82%) of a white solid: mp 100-101 °C; [R]20D 127 (c (15) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 1278. (16) Plobeck, N.; Powell, D. Tetrahedron: Asymmetry 2002, 13, 303.

0.5, CHCl3); IR (neat) 3050, 1607, 1576, 1461 cm-1; 1H NMR (CDCl3) δ 2.28 (s, 3 H), 2.50 (s, 6 H), 6.88 (s, 2 H), 7.46-7.47 (m, 3 H), 7.84-7.86 (m, 2 H), 8.83 (s, 1H); 13C NMR (CDCl3) δ 19.3, 21.5, 129.3, 129.9, 131.2, 132.9, 134.2, 135.7, 138.8, 142.1, 162.0. Anal. Calcd for C16H17NOS: C, 70.81; H, 6.31; N, 5.16. Found: C, 71.13, H, 6.23, N, 4.97. (S)-(+)-N-(p-Methoxybenzylidene)-2,4,6-trimethylphenylsulfinamide (12a): yield 78%; mp 67-68 °C; [R]20D 98.8 (c 0.5, CHCl3); IR (neat) 1594, 1072 cm-1; 1H NMR (CDCl3) δ 2.28 (s, 3 H), 2.50 (s, 6 H), 3.86 (s, 3 H), 6.85 (s, 2 H), 6.94 (d, J ) 9 Hz, 2 H), 7.79 (d, J ) 9 Hz, 2 H), 8.75 (s, 1 H); 13C NMR (CDCl3) δ 17.6, 19.8, 54.2, 113.0, 125.7, 129.5, 130.2, 134.4, 137.1, 140.3, 159.5, 161.8. Anal. Calcd for C17H19NO2S: C, 67.74; H, 6.35; N, 4.65. Found: C, 67.52, H, 6.44, N, 4.06. (S)-(+)-N-(4-Trifluoromethylbenzylidene)-2,4,6-trimethylphenylsulfinamide (12c): yield 78%; mp 92-93 °C; [R]20D 104.4 (c 0.5, CHCl3); IR (neat) 1571, 1449 cm-1; 1H NMR (CDCl3) δ 2.29 (s, 3 H), 2.49 (s, 6 H), 6.88 (s, 2 H), 7.71 (d, J ) 8 Hz, 2 H), 7.96 (d, J ) 8 Hz, 2 H), 8.87 (s, 1 H); 13C NMR (CDCl3) δ 19.3, 21.5, 125.3, 126.3, 130.1, 131.3, 134.3, 135.1, 137.1, 138.9, 142.4, 160.2. Anal. Calcd for C17H16F3NOS: C, 60.16; H, 4.75; N, 4.13. Found: C, 60.21 H, 4.79; N, 4.02. (S)-(+)-N-(4-Nitrobenzylidene)-2,4,6-trimethylphenylsulfinamide (12d): yield 79%; mp 141-142 °C; [R]20D 40.2 (c 0.5, CHCl3); IR (neat) 1583, 1534, 1344, 1105 cm-1; 1H NMR (CDCl3) δ 2.28 (s, 3 H), 2.48 (s, 6 H), 6.87 (s, 2 H), 8.0 (d, J ) 11 Hz, 2 H), 8.29 (d, J ) 11 Hz, 2 H), 8.89 (s, 1 H); 13C NMR (CDCl3) δ 19.2, 21.5, 124.5, 130.5, 131.4, 134.8, 138.9, 139.2, 142.5, 150.2, 159.6. Anal. Calcd for C16H16N2O3S: C, 60.74; H, 5.10; N, 8.85. Found: C, 61.16, H, 5.02, N, 8.37. Typical One-Pot Synthesis of Aziridine 2-Phosphonates. (SS,2S,3R)-(+)-N-(2,4,6-Mesitylsulfinyl)-3-phenylaziridine-2-phosphonate (13b). In a 25-mL, two-neck, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon were placed 0.10 g (0.368 mmol) of (+)-12b and 0.21 g (0.737 mmol) of diethyl 2-iodomethylphosphonate in THF (10 mL). The solution was cooled to -78 °C, and after 10 min, 0.737 mL (0.737 mmol, 1 M in THF) of LiHMDS was added via syringe. After being stirred at this temperature for 30 min, the solution was quenched by addition of saturated aqueous NH4Cl (5 mL) and the solution was warmed to room temperature. At this time, the reaction mixture was diluted with water (10 mL) and the solution was extracted with EtOAc (2 × 25 mL). The combined organic phases were washed with saturated sodium thiosulfate (10 mL) and brine (15 mL), dried (Na2SO4), and concentrated to give a yellow oil. Flash chromatography (EtOAc-hexane, 6:4) afforded 0.121 g (78%) as a colorless oil: [R]20D 56.4 (c 0.5, CHCl3); IR (neat) 2976, 2927, 1244, 1103 cm-1; 1H NMR (CDCl3) δ 0.97 (t, J ) 8 Hz, 3 H), 1.06 (t, J ) 8 Hz, 3 H), 2.22 (s, 3 H), 2.50 (s, 6 H), 2.68 (dd, 2JHP ) 16.4 Hz, J ) 7.6 Hz, 1 H), 3.50-3.53 (m, 1 H), 3.71-3.86 (m, 3 H), 4.10 (dd, 3JCP ) 7.8 Hz, J ) 7.6 Hz, 1 H), 6.70 (s, 2 H), 7.08-7.15 (m, 5 H); 13C NMR (CDCl3) δ 16.6 (d, 3JCP ) 5.7 Hz), 19.6, 21.5, 34.1 (d, 1 JCP ) 229.4 Hz), 38.5, 62.5 (2 x d, 2JCP ) 6.1 Hz), 128.2, 128.3, 128.4, 131.5, 133.4, 136.1, 138.5, 142.1; 31P NMR (CDCl3) δ 19.0; HRMS calcd for C21H28NO4PS (M + Na) 444.1374, found 444.1364. (SS,2S,3R)-(+)-N-(2,4,6-Mesitylsulfinyl)-3-(p-methoxyphenyl)aziridine-2-phosphonate (13a): yield 75%; [R]20D 37.7 (c 1.0, CHCl3); IR (neat) 2979, 2931, 1612, 1026 cm-1; 1H NMR (CDCl3) δ 1.15 (2 x t, J ) 6.4 Hz, 6 H), 2.32 (s, 3 H), 2.60 (s, 6 H), 2.71 (dd, 2JHP ) 16.8, J ) 6.8 Hz, 1 H), 3.69-3.70 (m, 1 H), 3.71 (s, 3 H), 3.88-3.96 (m, 3 H). 4.10-4.15 (m, 1 H), 6.77 (d, J ) 7.6 Hz, 2 H), 6.87 (s, 2 H), 7.14 (d, J ) 7.6 Hz, 2 H); 13C NMR (CDCl3) δ 16.7, 19.6, 21.5, 34.2 (d, 1JCP ) 208.6 Hz), 38.1, 55.6 (2 x d, 2JCP ) 6.0 Hz), 113.7, 125.3, 129.6, 131.5, 136.2, 138.5, 142.0, 159.6; 31P NMR (CDCl3) δ 19.2; HRMS calcd for C22H30NO5PS (M + Na) 474.1480, found 444.1474. Typical Procedure for the Synthesis of R-Chloro-βaminophosphonates 15 and 16. In a 50-mL, round-bottom flask equipped with a magnetic stirring bar, rubber septum,

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Davis et al. and argon balloon were placed 0.05 g (0.166 mmol) of (S)-(+)12a and 0.052 g (0.322 mmol) of dimethyl chloromethylphosphonate in THF (20 mL). The mixture was cooled to -78 °C, and after 10 min, 0.166 mL (0.322 mmol, 2.0 M in cyclohexane) of n-BuLi was added quickly via syringe. After being stirred at this temperature for 30 min, the reaction mixture was quenched by addition of saturated aqueous NH4Cl (5 mL), warmed to room temperature, and diluted with H2O (10 mL). The solution was extracted with Et2O (2 × 10 mL), and the combined organic phases were dried (Na2SO4) and concentrated to give a yellow oil. Purification by flash chromatography (EtOAC-hexane, 6:1) gave 0.053 g (70%) of an inseparable mixture of 15a/16a as an oil in a ratio of 77:23. Typical Deprotection Procedure. Diethyl (2S,3R)-(-)-3-Phenylaziridine-2-phosphonate (17b). In a 25-mL, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed 0.10 g (0.237 mmol) of (+)-13b in THF (10 mL). The solution was cooled to -78 °C, and after 10 min, 0.156 mL (0.468 mmol, 3.0 M in Et2O) of MeMgBr was added dropwise via syringe. After being stirred at this temperature for 2 h, the reaction mixture was quenched by addition of saturated aqueous NH4Cl (5 mL) and the solution was warmed to room temperature. At this time, the solution was extracted with EtOAc (2 × 25 mL), and the combined organic phases were dried (Na2SO4) and concentrated to give a green oil. Flash chromatography (CH2Cl2EtOAc, 4:1) afforded 0.466 g (77%) of colorless oil: [R]20D -36.1 (c 0.80, CHCl3) [lit.2 [R]20D -36.5 (c 0.85, CHCl3)]. Spectral properties were consistent with literature values.2 Diethyl (2S,3R)-(-)-3-(p-methoxyphenyl)aziridine-2phosphonate (17a): yield 72%; mp 33-34 °C; [R]20D -25.0 (c 0.65, CHCl3); IR (KBr) 3237, 1250, 1031 cm-1; 1H NMR(CDCl3) δ 1.07-1.19 (m, 6 H), 1.50 (brs, 1 H), 2.46 (m, 1 H), 3.30-3.55 (m, 2 H), 3.70-3.95 (m, 6 H), 6.83 (d, J ) 8 Hz, 2 H), 7.297.41 (brs, 2 H); 13C NMR(CDCl3) δ 16.9, 31.4(d, 1JCP ) 218 Hz), 37.2, 55.9, 62.3 (t, 2JCP ) 16.2 Hz), 113.9, 129.4, 129.9, 159.7; 31P NMR (CDCl3) δ 22.26. Anal. Calcd. for

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C13H20NO4P: C, 54.73; H, 7.07; N, 4.91. Found: C, 54.86; H, 7.37; N, 4.83. (SS,2S,3R)-(+)-N-[1-(2-Methylpropane-2-sulfinyl)-3-(4trifluoromethylphenyl)aziridin-2-yl]phosphonic Acid Diethyl Ester (8b). In a 25-mL, two-neck, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon were placed 0.1 g (0.365 mmol) of (+)-7b and 0.203 g (0.731 mmol) of diethyl 2-iodomethylphosphonate in THF (10 mL). The solution was cooled to -78 °C, and after 10 min, 0.731 mL (1 M in THF, 0.731 mmol) of LiHMDS was added via syringe. After being stirred at this temperature for 30 min, the solution was quenched by addition of saturated aqueous NH4Cl (5 mL) and warmed to room temperature. The solution was diluted with water (10 mL), and the reaction mixture was extracted with EtOAc (2 × 25 mL). The combined organic phases were washed with saturated sodium thiosulfate (10 mL) and brine (15 mL), dried (Na2SO4), and concentrated. Flash chromatography (EtOAc-hexane, 6:4) afforded 0.112 g (72%) as a colorless oil: [R]20D 42.4 (c 1.25, CHCl3); IR (neat) 2989, 1314, 1267, 2273 cm-1; 1H NMR (CDCl3) δ 1.05 (t, J ) 6.8 Hz, 3 H), 1.15 (t, J ) 6.8 Hz, 3 H), 1.18 (s, 9 H), 2.55 (dd, 2J HP ) 15.2 Hz, J ) 7.2 Hz, 1 H), 3.72-3.81 (m, 2 H), 3.853.95 (m, 3 H), 7.52-7.57 (m, 4 H); 13C NMR (CDCl3) δ 16.6 (2 x d, 3JCP ) 5.5 Hz), 23.0, 33.8 (d, 1JCP ) 209.7 Hz), 35.7, 57.9, 62.8 (d, J ) 5.5 Hz), 125.4, 128.8, 129.4, 130.7, 137.4; 31P NMR (CDCl3) δ 17.70; HRMS calcd for C17H25F3NO4PS (M + Na) 450.1094, found 450.1092

Acknowledgment. This work was supported by the National Institutes of General Medical Sciences (NIGMS 57870). Supporting Information Available: Spectral data for compounds where only HRMS is available. This material is available free of charge via the Internet at http://pubs.acs.org. JO030142M